It is believed that αVβ3 and αVβ5 integrin receptor antagonists can be useful for the treatment of a wide variety of disease states and can represent a new class of drugs. The αVβ3/αVβ5 integrins are cell adhesion receptors which specifically recognize matrix proteins containing the cell-adhesion tripeptide motif arginine-glycine-aspartic acid (RGD). Both integrins are expressed on endothelial cells, smooth muscle cells, osteoclasts and tumor cells, behaving as mediators of cell adhesion, migration, and survival.
Expression of these integrins is typically minimal on normal blood vessels but can be significantly up-regulated in response to a variety of stimuli, leading to such conditions as angiogenesis. Based on results from in vivo animal models, antagonists of αVβ3/αVβ5 integrins may be useful for the treatment of osteoporosis, growth and metastasis of malignant tumors, diabetic retinopathy, arthritis and coronary restenosis (Ref: Miller, W. H., Keenan, R. M.; Willette, R. N.; Lark, M. W., DDT2000, 5 (9), 397-408).
It is an object of the present invention to provide tricyclic indanyl derivatives which are useful αVβ3, αV55 or dual αvβ3/αVβ5 integrin receptor antagonists for the treatment of a wide variety of integrin-mediated disease states. It is another object of the present invention to provide a process for preparing tricyclic indanyl compounds, compositions, intermediates and derivatives thereof.